Lung cancer remains the leading cause of cancer death, killing more patients than breast, colon, and prostate cancers combined. Although tobacco smoke is the predominant risk factor for development of lung cancer, some patients develop the disease without a history of tobacco smoking. About 10 - 15% of all lung cancers occur in lilfetime never smokers. This figure will increase as the proportion of never smokers increases in the population. Even at present rates, lung cancer in never smokers, if considered a separate disease, is 7th to 9th top cause of cancer death. The growing number of never smokers in the USA and other countries emphasizes the importance of understanding the epidemiology and biology underlying lung cancer in this group. Epidemiological, molecular and clinical data suggest that molecular mechanisms of lung cancer may differ in smokers and nonsmokers, making lung cancer in never smokers a different disease compared to the lung cancer in smokers. The genetic epidemiology of lung cancer in never smokers has not been well explored, largely because of difficulties in accruing the needed sample size for association studies. We propose a multicenter (total 22 sites from North America, Israel, and Europe) genomewide association study of lung cancer in never smokers with the following specific aims: Aim 1: Discovery phase: To identify candidate SNPs influencing the risk for lung cancer in never smokers. This phase will include 1553 never smoker lung cancer cases and 1553 controls matched on age, gender, and study site. Aim 2: Replication phase: To perform replication analysis of significant SNPs identified in the Discovery phase, using an independent set of cases and controls from International Lung Cancer Consortium (ILCCO) studies. There will be 1581 independent cases and 1581 matched controls in this phase. Aim 3: To identify and explore pathways associated with the risk of lung cancer in never smokers. To explore the effects of gene-gene and gene-environment interactions on lung cancer risk in never smokers. This will be the first GWAS aiming at identifying the genetic control of susceptibility to lung cancer in Caucasian never smokers. We will combine the available resources from the multiple sites to achieve the sample size sufficient for this study. The study will identify genetic architecture of the predisposition to the lung cancer in never smokers. PUBLIC HEALTH RELEVANCE: Although tobacco smoke is the predominant risk factor for development of lung cancer, about 10 - 15% patients develop the disease without smoking, making lung cancer in never smokers 7th to 9th top cause of cancer death in the US. We propose a multicenter genomewide association study of lung cancer in Caucasian never smokers that will use data from a total of 22 sites from the North America, Israel, and Europe. This project will identify candidate regions in the genome associated with risk of lung cancer in people who have never smoked, which will help prevention and treatment efforts.